Preparation of thiazoles

ABSTRACT

The present invention is directed to a process for preparing a compound having the formula: 
                         
wherein R is a range of organic groups and X is a leaving group. The process may include reacting a compound of the formula
 
                         
with a water-removing reagent. Also, when X is a halogen, the process may include reacting a compound of the formula
 
                         
with a halogenating agent or a sulfonylating agent. Alternatively, when X is a halogen, the process may be carried out by reacting a compound of the formula IV
 
                         
where R 2  and R 3  are defined organic groups with a compound of the formula halogen-C(—O)—O—C1 -C8alkyl, halogen-C(—O)—O-aryl or halogen-C(—O)—O-benzyl.

This application is a divisional application of U.S. Ser. No.10/400,826, filed Mar. 27, 2003, now U.S. Pat. No. 7,161,011 which is adivisional application of U.S. Ser. No. 09/331,433, filed Jun. 18, 1999,now U.S. Pat. No. 6,548,676, which is a National Stage of InternationalApplication No. PCT/EP97/07088 filed Dec. 17, 1997, which claimspriority to CH 3125/96 filed Dec. 19, 1996, the contents of which areincorporated herein by reference.

The invention relates to a process for the preparation of a compound ofthe formula

and, where applicable, its E/Z-isomers, mixtures of E/Z-isomers and/ortautomers and acid addition products thereof, in each case in free formor in salt form, wherein

-   R is unsubstituted or substituted C₁C₁₂alkyl, unsubstituted or    substituted C₂-C₄alkenyl, unsubstituted or substituted C₂-C₄alkynyl,    unsubstituted or substituted C₃-C₆cycloalkyl, unsubstituted or    substituted aryl, unsubstituted or substituted heteroaryl, or —SR₁;-   R₁ is unsubstituted or substituted C₁C₁₂alkyl, unsubstituted or    substituted C₂-C₄alkenyl, unsubstituted or substituted C₂-C₄alkenyl,    unsubstituted or substituted C₂-C₄alkynyl, unsubstituted or    substituted cycloalkyl, unsubstituted or substituted aryl or    unsubstituted or substituted heteroaryl and-   X is a leaving group; which comprises    a) reacting a compound of the formula

-   -   or, where applicable, an E/Z-isomer, a mixture of E/Z-isomers        and/or a tautomer thereof, in each case in free form or in salt        form, wherein R is as defined for formula (I), with a water        removing reagent; or        b) for the preparation of a compound of formula (I) wherein X is        halogen or a sulfonate, reacting a compound of the formula

and, where applicable, its E/Z-isomers, mixtures of E/Z-isomers and/ortautomers arid acid addition products thereof, in each case in free formor in salt form, wherein R is as defined for formula (I), with ahalogenating agent or a sulfonylating agent; orc) for the preparation of a compound of formula (I) wherein X ishalogen, reacting a compound of the formula

and, where applicable, its E/Z-isomers, mixtures of E/Z-isomers and/ortautomers and acid addition products thereof, in each case in free formor in salt form, wherein

-   R is as defined for formula (I); and-   R₂ and R₃ are each independently of the other H, C₁-C₆alkyl,    C₃-C₆cycloalkyl, phenyl or benzyl or, together with the nitrogen    atom to which they are bonded, form a five- to seven-membered ring    in which a —CH₂— group has optionally been replaced by a hetero atom    selected from the group consisting of 0 and S, or by NR₉, and    wherein the carbon-chain of the five- to seven-membered ring is    unsubstituted or is mono- or di-substituted by C₁-C₄alkyl; and R₉ is    an organic radical;    with a compound of the formula halogen-C(═O)—O—C₁-C₈alkyl,    halogen-C(═O)—O-aryl or halogen-C(═O)—O-benzyl, preferably with    ethyl chloroformate;    and in each case, if desired, converting a compound of formula (I)    obtainable in accordance with the process or by another method, or    an E/Z-isomer or tautomer and acid addition products thereof, in    each case in free form or in salt form, into a different compound of    formula (I) or an E/Z-isomer or tautomer and acid addition products    thereof, in each case in free form or in salt form, separating a    mixture of E/Z-isomers obtainable in accordance with the process and    isolating the desired isomer, and/or converting a free compound of    formula (I) obtainable in accordance with the process or by another    method, or an E/Z-isomer or tautomer thereof, into a salt or    converting a salt, obtainable in accordance with the process or by    another method, of a compound of formula (I) or of an E/Z-isomer or    tautomer thereof into the free compound of formula (I) or an    E/Z-isomer or tautomer thereof or into a different salt.

Methods of synthesis for the compounds of formula (I) are described inthe literature. However, they are not completely satisfactory and thereis therefore the need to make available improved processes for thepreparation of those compounds. The compounds of formula (I) arevaluable intermediates in the preparation of other compounds that can beused in the preparation of compounds—especially of formula (A) belowhaving pesticidal activity. Accordingly, the invention relates also to aprocess for the preparation of a compound of the formula

and, where applicable, their E/Z-isomers, mixtures of E/Z-isomers and/ortautomers and acid addition products thereof, in each case in free formor in salt form, wherein

-   Q is CH or N,-   Y is NO₂ or CN,-   Z is CHR₆, O, NR₆ or S,    R₄ and R₅ are either each independently of the other hydrogen or    unsubstituted or R₇-substituted alkyl, or together form an alkylene    bridge having two or three carbon atoms, and said alkylene bridge    may additionally contain a hetero atom selected from the group    consisting of NR₈, O and S;-   R₆ is H or unsubstituted or R₇-substituted alkyl,-   R₇ is unsubstituted or substituted aryl or heteroaryl, and-   R₈ is H or C₁-C₁₂alkyl;    which comprises reacting a compound of formula (I), prepared by the    process described above, with a compound of the formula

or, where applicable, an E/Z-isomer, a mixture of E/Z-isomers and/or atautomer thereof, in each case in free form or in salt form, wherein Q,Y, Z, R₄ and R₅ are as defined above for formula (A), to form a compoundof the formula

or, where applicable, an E/Z-isomer, a mixture of E/Z-isomers and/or atautomer and acid addition products thereof, in each case in free formor in salt form, wherein R is as defined above for formula (I) andQ, Y, Z, R₄ and R₅ are as defined above for formula (A), andconverting the compound of formula (C) by means of a halogenating agentinto a compound of formula (A).

The present invention relates also to a process for the preparation of acompound of formula (C) and, where applicable, its E/Z-isomers, mixturesof E/Z-isomers and/or tautomers and acid addition products thereof, ineach case in free form or in salt form, which comprises reacting acompound of the formula (I) with a compound of the formula (B); and aprocess for the preparation of a compound of formula (A) and, whereapplicable, its E/Z-isomers, mixtures of E/Z-isomers and/or tautomersand acid addition products thereof, in each case in free form or in saltform, which comprises reacting a compound of the formula: (C) with ahalogenating agent.

Some compounds of formulae (I) to (VIII) and (A) to (C) definedhereinbefore and herein-after contain asymmetric carbon atoms, as aresult of which the compounds may occur in optically active form. Thecorresponding formulae are intended to include all those possibleisomeric forms as well as mixtures thereof, for example racemates ormixtures of E/Z-isomers.

The general terms used hereinbefore and hereinafter have the meaningsgiven below, unless defined otherwise:

Unless defined otherwise, carbon-containing groups and compounds eachcontain from 1 up to and including 8, preferably from 1 up to andincluding 6, especially from 1 up to and including 4, more especially 1or 2, carbon atoms.

Alkyl—both as a group per se and as a structural element of other groupsand compounds, such as haloalkyl, arylalkyl or hydroxyalkyl—ispreferably, in each case giving due consideration to the number ofcarbon atoms contained in the group or compound in question, eitherstraight-chained, i.e. methyl, ethyl, propyl, butyl, pentyl or hexyl, orbranched, for example isopropyl, isobutyl, sec-butyl, tert-butyl,isopentyl, neopentyl or isohexyl.

Alkenyl—both as a group per se and as a structural element of othergroups and compounds, such as haloalkenyl or arylalkenyl—is, in eachcase giving due consideration to the number of carbon atoms contained inthe group or compound in question, either straight-chained, for examplevinyl, 1-methylvinyl, allyl, 1-butenyl or 2-hexenyl, or branched, forexample isopropenyl.

Alkynyl—both as a group per se and as a structural element of othergroups and compounds, such as haloalkynyl—is, in each case giving dueconsideration to the number of carbon atoms contained in the group orcompound in question, either straight-chained, for example propargyl,2-butynyl or 5-hexynyl, or branched, for example 2-ethynylpropyl or2-propargylisopropyl.

C₃-C₆Cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,especially cyclohexyl.

Aryl is phenyl or naphthyl, especially phenyl.

Heteroaryl is understood as being a five- to seven-membered monocyclicaromatic ring that contains from one to three hetero atoms selected fromthe group consisting of N, O and S, especially N and S, or a bicyclicheteroaryl that may contain either in only one ring—such as, forexample, in quinolinyl, quinoxalinyl, indolinyl, benzothiophenyl orbenzofuranyl—or in both rings—such as, for example, in pteridinyl orpurinyl—independently of one another, one or more hetero atoms selectedfrom N, O and S. Preference is given to pyridyl, pynmidinyl, thiazolyland benzothiazolyl, especially thiazolyl.

Halogen—both as a group per se and as a structural element of othergroups and compounds, such as haloalkyl, haloalkenyl and haloalkynyl—isfluorine, chlorine, bromine or iodine, especially fluorine, chlorine orbromine, more especially chlorine or bromine, very especially chlorine.

Halo-substituted carbon-containing groups and compounds, such ashaloalkyl or haloalkenyl, may be partially halogenated orperhalogenated, the halogen substituents in the case ofmulti-halogenation being the same or different. Examples ofhaloalkyl—both as a group per se and as a structural element of othergroups and compounds, such as haloalkenyl—are methyl substituted fromone to three times by fluorine, chlorine and/or by bromine, such as CHF₂or CF₃; ethyl substituted from one to five times by fluorine, chlorineand/or by bromine, such as CH₂CF₃, CF₂CF₃, CF₂CCl₃, CF₂CHCl₂, CF₂CHF₂,CF₂CFCl₂, CF₂CHBr₂, CF₂CHClF, CF₂CHBrF or CClFCHClF; propyl or isopropylsubstituted from one to seven times by fluorine, chlorine and/or bybromine, such as CH₂CHBrCH₂Br, CF₂CHFCF₃, CH₂CF₂CF₃ or CH(CF₃)₂; andbutyl or an isomer thereof substituted from one to nine times byfluorine, chorine and/or by bromine, such as CF(CF₃)CHFCF₃ orCH₂(CF₂)₂CF₃. Haloalkenyl is, for example, CH₂CH═CHCl, CH₂CH═CCl₂,CH₂CF═CF₂ or CH₂CH═CHCH₂Br.

Some compounds of formulae (I) to (VIII) and (A) to (C) may be in theform of tautomers. Therefore, hereinbefore and hereinafter thosecompounds are to be understood as including also the correspondingtautomers, even if the latter are not mentioned specifically in everycase.

Compounds of formulae (I) to (VIII) and (A) to (C) that have at leastone basic centre are able to form, for example, acid addition salts.These are formed, for example, with strong inorganic acids, such asmineral acids, for example perchloric acid, sulfuric acid, nitric acid,nitrous acid, a phosphoric acid or a hydrohalic acid, with strongorganic carboxylic acids, such as unsubstituted or substituted, forexample halo-substituted, C₁-C₄alkane-carboxylic acids, for exampleacetic acid, saturated or unsaturated dicarboxylic acids, for exampleoxalic, malonic, succinic, maleic, fumanc or phthalic acid,hydroxycarboxylic acids, for example ascorbic, lactic, malic, tartaricor citric acid, or benzoic acid, or with organic sulfonic acids, such asunsubstituted or substituted, for example halo-substituted, C₁-C₄alkane-or arylsulfonic acids, for example methane- or p-toluene-sulfonic acid.Moreover, compounds of formulae (I) to (IV) and (A) to (C) having atleast one acid group, for example wherein R is —CH₂—COO-M, are able toform salts with bases. Suitable salts with bases are, for example, metalsalts, such as alkali metal or alkaline earth metal salts, for examplesodium, potassium or magnesium salts, or salts with ammonia or anorganic amine, such as morpholine, piperidine, pyrrolidine, a mono-, di-or tri-lower alkylamine, for example ethyl-, diethyl-, triethyl- ordimethyl-propyl-amine, or a mono-, di- or tri-hydroxy-lower alkylamine,for example mono-, di- or tri-ethanolamine. Furthermore, correspondinginternal salts may be formed. Hereinbefore and hereinafter, thecompounds of formula (I) are to be understood as being both thecompounds of formulae (I) to (VIII) and (A) to (C) in free form and thecorresponding salts. The same applies to tautomers of compounds offormulae (I) to (VIII) and (A) to (C) and their salts. Preference is ineach case generally given to a process for the preparation of the freeform.

Add addition products are understood as being products which areobtainable by the addition of an acid, preferably an inorganic acid, toa double bond, especially to a double bond of a heterocycle. Forexample, addition of an acid HX₁, wherein the anion X₁ has the meaningsas given for X in formula (I), to a compound of the formula (I) asdefined above may result in the compound of the formula

The artisan is well aware, that an acid HX₁ can easily be split off fromthe said acid addition product; e.g. the compound of the formula (IX)can be converted into the compound of the formula (I). Therefore, thecompounds of formula (I), (III), (IV), (VI) to (VIII), (A) and (C) arehereinbefore and hereinafter to be understood as being both thecompounds of the formulae (I), (III), (IV), (VI) to (VIII), (A) and (C)and the corresponding acid addition products, in free form and the saltsthereof, even if not all the forms are specifically mentioned in everycase.

Hereinbefore and hereinafter a leaving group is understood as being anyremovable group that is customarily suitable in chemical reactions, suchas is known to the person skilled in the art; for example halides,especially chloride or bromide, H₂O, SH, CN, sulfonates, sulfinates,NO₃, NO₂ or SO₃; special preference is given to chloride or bromide andsulfonates. Especially preferred leaving groups are mentioned in theindividual processes.

Within the scope of the invention preference is given to the processesmentioned hereinbefore and hereinafter for the preparation of compoundsof formulae (I) to (IV) and (VI) wherein

-   (1) R is unsubstituted or halo- or hydroxy-substituted C₁-C₁₂alkyl,    unsubstituted or halo-substituted aryl-C₁-C₄alkyl, unsubstituted or    halo-substituted heteroaryl-C₁-C₄alkyl, arylC₂-C₄alkenyl,    heteroaryl-C₂-C₄alkenyl, unsubstituted or halo-substituted    C₂-C₄alkenyl, C₂-C₄-alkynyl, aryl-C₂-C₄alkynyl,    heteroaryl-C₂-C₄alkyflyl, C₄-C₆cycloalkyl, unsubstituted or    halo-substituted aryl, unsubstituted or halo-substituted heteroaryl,    —CH₂—COO—C₁-C₈alkyl,    —CH₂—CO—C₁-C₈alkyl, SR₁ or —CH₂—COO-M, wherein M is hydrogen or a    cation; especially C₁-C₄alkyl, hydroxy-C₁-C₄alkyl, C₃-C₄alkenyl,    C₃-C₄alkynyl, chloro-C₃-C₄alkenyl, unsubstituted or    chlorine-substituted phenyl, unsubstituted or chlorine-substituted    benzyl, heteroaryl, cyclohexyl, —CH₂—COO—C₁-C₄alkyl more especially    C₁-C₄alkyl, phenyl, benzyl, cyclohexyl, benzothiazol-2-yl or    —CH₂—COO-ethyl; very especially phenyl or benzyl;-   (2) X is methylsulfonate, trifluoromethylsulfonate,    p-toluenesulfonate or halogen, especially chlorine or bromine;-   (3) R is —(CH₂)_(n)—SR₁ and R₁ is C₁-C₈alkyl, aryl-C₁-C₄alkyl,    heteroaryl-C₁-C₄alkyl, C₂-C₄alkenyl, aryl-C₂-C₄alkenyl,    heteroaryl-C₂-C₄alkenyl, C₂-C₄alkynyl, aryl-C₂-C₄alkynyl,    heteroaryl-C₂-C₄alkynyl, cyclohexyl, aryl, arylthio, heteroaryl,    heteroarylthio; or heteroaryl or heteroarylthio which are both    substituted with —CH₂—X₁ or formyl;-   X₁ is as defined in claim 1 for X;-   and n is 1 to 8;    especially R₁ is C₁-C₄alkyl, cyclohexyl, aryl or

X₁ is halogen or hydroxy; and n is 1 or 2.

Also preferred are compounds of the formula (IV), wherein

-   (4) R₂ and R₃ independently of each other are H, C₁-C₆-alkyl,    C₃-C₆-cycloalkyl, phenyl or benzyl, or together with the N-atom to    which they are bonded form a five- to seven-membered ring, wherein    one CH₂-group may be replaced by a heteroatom selected from the    group consisting of O and S, or by NR₉, and wherein the carbon-chain    of the five- to seven-membered ring may be substituted by one or two    C₁-C₄-alkyl groups; and-   R₉ is H, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, phenyl or benzyl;    especially wherein R₂ and R₃ are independently of each other H,    C₁-C₆-alkyl or C₃-C₆-cycloalkyl, or together with the N-atom to    which they are bonded form a five- to seven-membered ring, wherein    one CH₂-group may be replaced by a heteroatom selected from the    group consisting of O and S, or by NR₉, and-   R₉ is H, C₁-C₆-alkyl, C₃-C₆-cycloalkyl, phenyl or benzyl;    especially wherein R₂ and R₃ are independently of each other is    C₁-C₆-alkyl, or together with the N-atom to which they are bonded    form a five- to seven-membered ring, wherein one CH₂-group may be    replaced by a heteroatom selected from the group consisting of O and    S, or by NR₉, and-   R₉ is C₁-C₆-alkyl, C₃-C₆-cycloalkyl, phenyl or benzyl;    very especially wherein R₂ and R₃ are independently of each other    are C₁-C₄-Alkyl, or together form —CH₂—CH₂—CH₂—CH₂—,    —CH₂—CH₂—CH₂—CH₂—CH₂—, —CH₂—CH₂—O—CH₂—CH₂— or    —CH₂—CH₂—N(R₉)—CH₂—CH₂—, and R₉ is C₁-C₆-alkyl, phenyl or benzyl.

Within the scope of the invention preference is given to a process forthe preparation of a compound of formulae (A) and (C) wherein

-   (5) R₄ and R₅ are either each independently of the other hydrogen or    unsubstituted or R₇-substituted alkyl, or together form an alkylene    bridge having two or three carbon atoms, and said alkylene bridge    may additionally contain a group NR₈ or a hetero atom selected from    the group consisting of O and S; and R₈ is C₁-C₄alkyl;    especially, R₄ and R₅ are each hydrogen or together form a two- or    three-membered alkylene bridge that may additionally contain a    hetero atom from the group consisting of NR₈ and O, and R₈ is methyl    or ethyl;    more especially, R₄ and R₅ together are —CH₂—O—CH₂—, —CH₂—CH₂—CH₂—    or —CH₂—CH₂—. The present invention relates also to a process for    the preparation of a compound of formula (II) and, where applicable,    its E/Z-isomers, mixtures of E/Z-isomers and/or tautomers, in each    case in free form or in salt form, which comprises    d) reacting a compound of the formula

or, where applicable, an E/Z-isomer, a mixture of E/Z-isomers and/or atautomer thereof, in each case in free form or in salt form, which isknown or can be prepared by methods known per se and wherein R is asdefined for formula (I), with glycidyl aldehyde of the formula

and in each case, if desired, converting a compound of formula (II)obtainable in accordance with the process or by another method, or anE/Z-isomer or tautomer thereof, in each case in free form or in saltform, into a different compound of formula (II) or an E/Z-isomer ortautomer thereof, in each case in free form or in salt form, separatinga mixture of E/Z-isomers obtainable in accordance with the process andisolating the desired isomer, and/or converting a free compound offormula (II) obtainable in accordance with the process or by anothermethod, or an E/Z-isomer or tautomer thereof, into a salt or convertinga salt, obtainable in accordance with the process or by another method,of a compound of formula (II) or of an E/Z-isomer or tautomer thereofinto the free compound of formula (II) or an E/Z-isomer or tautomerthereof or into a different salt.

The present invention relates also to a process for the preparation of acompound of formula (III) and, where applicable, its E/Z-isomers,mixtures of E/Z-isomers and/or tautomers and acid addition productsthereof, in each case in free form or in salt form, which compriseseither

e) reacting a compound of formula (II) or, where applicable, anE/Z-isomer, a mixture of E/Z-isomers and/or a tautomer thereof, in eachcase in free form or in salt form, with an acid, or

f) reacting a compound of the formula

and, where applicable, its E/Z-isomers, mixtures of E/Z-isomers and/ortautomers and acid addition products thereof, in each case in free formor in salt form, wherein

-   R is as defined for formula (I), with hydrogen in the presence of a    hydrogenation catalyst, and in each case, if desired, converting a    compound of formula (III) obtainable in accordance with the process    or by another method, or an E/Z-isomer or tautomer thereof, in each    case in free form or in salt form, into a different compound of    formula (III) or an E/Z-isomer or tautomer thereof, in each case in    free form or in salt form, separating a mixture of E/Z-isomers    obtainable in accordance with the process and isolating the desired    isomer, and/or converting a free compound of formula (III)    obtainable in accordance with the process or by another method, or    an E/Z-isomer or tautomer thereof, into a salt or converting a salt,    obtainable in accordance with the process or by another method, of a    compound of formula (III) or of an E/Z-isomer or tautomer thereof    into the free compound of formula (III) or an E/Z-isomer or tautomer    thereof or into a different salt.

The present invention relates also to a process for the preparation of acompound of formula (IV) and, where applicable, its E/Z-isomers,mixtures of E/Z-isomers and/or tautomers, in each case in free form orin salt form,

wherein R, R₁, R₂ and R₃ are as defined above for compounds of formulae(I) and (IV), which comprises

g) reacting a compound of the formula

and, where applicable, its E/Z-isomers, mixtures of E/Z-isomers and/ortautomers and acid addition products thereof, in each case in free formor in salt form, which is known or can be prepared by methods known perse and wherein R₂ and R₃ are as defined above for formula (IV), with acompound of the formula R—X₂, which is known or can be prepared bymethods known per se and wherein R is as defined in formula (I) and X₂is a leaving group, such as an alkyl-, haloalkyl- or aryl-sulfonate orhalogen, especially bromine or chlorine;and in each case, if desired, converting a compound of formula (IV)obtainable in accordance with the process or by another method, or anE/Z-isomer or tautomer thereof, in each case in free form or in saltform, into a different compound of formula (IV) or an E/Z-isomer ortautomer thereof, in each case in free form or in salt form, separatinga mixture of E/Z-isomers obtainable in accordance with the process andisolating the desired isomer, and/or converting a free compound offormula (IV) obtainable in accordance with the process or by anothermethod, or an E/Z-isomer or tautomer thereof, into a salt or convertinga salt, obtainable in accordance with the process or by another method,of a compound of formula (IV) or of an E/Z-isomer or tautomer thereofinto the free compound of formula (IV) or an E/Z-isomer or tautomerthereof or into a different salt.

The present invention relates also to a process for the preparation of acompound of formula (VI) and, where applicable, its E/Z-isomers,mixtures of E/Z-isomers and/or tautomers, in each case in free form orin salt form, which comprises

h) formulating a compound of the formula

or, where applicable, an E/Z-isomer, a mixture of E/Z-isomers and/or atautomer and acid addition products thereof, in each case in free formor in salt form, which is known or can be prepared by methods known perse and wherein R is as defined above for formula (I),and in each case, if desired, converting a compound of formula (VI)obtainable in accordance with the process or by another method, or anE/Z-isomer or tautomer thereof, in each case in free form or in saltform, into a different compound of formula (VI) or an E/Z-isomer ortautomer thereof, in each case in free form or in salt form, separatinga mixture of E/Z-isomers obtainable in accordance with the process andisolating the desired isomer, and/or converting a free compound offormula (VI) obtainable in accordance with the process or by anothermethod, or an E/Z-isomer or tautomer thereof, into a salt or convertinga salt, obtainable in accordance with the process or by another method,of a compound of formula (VI) or of an E/Z-isomer or tautomer thereofinto the free compound of formula (VI) or an E/Z-isomer or tautomerthereof or into a different salt.

With regard to the E/Z-isomers and tautomers, in free form or in saltform, of the starting materials of formulae (II) to (VIII) mentionedhereinbefore and hereinafter, the statements made above with respect tothe E/Z-isomers and tautomers, in free form or in salt form, of thecompounds of formula (I) apply analogously.

The reactions of variants a) to h) described hereinbefore andhereinafter are carried out in a manner known per se, for example in theabsence or, customarily, in the presence of a suitable solvent ordiluent or of a mixture thereof, the reactions being carried out, asrequired, with cooling, at room temperature or with heating, for examplein a temperature range of approximately from −80° C. to the boilingtemperature of the reaction medium, preferably from approximately −20°C. to approximately +120° C., especially from 20° C. to 80° C., and, ifnecessary, in a closed vessel, under pressure, under an inert gasatmosphere and/or under anhydrous conditions. Especially advantageousreaction conditions can be taken from the Examples.

The reactants can in each case be reacted with one another as such, i.e.without the addition of a solvent or diluent, for example in the moltenstate. However, the addition of an inert solvent or diluent or of amixture thereof is in most cases advantageous. There may be mentioned asexamples of such solvents and diluents: aromatic, aliphatic andalicyclic hydrocarbons and halogenated hydrocarbons, such as benzene,toluene, xylene, mesitylene, Tetralin, chlorobenzene, dichlorobenzene,bromobenzene, petroleum ether, hexane, cyclohexane, dichloromethane,trichloromethane, tetrachloromethane, dichloroethane, trichloroethene ortetrachloroethene; esters, such as ethyl acetate; ethers, such asdiethyl ether, dipropyl ether, diisopropyl ether, dibutyl ether,tert-butyl methyl ether, ethylene glycol monomethyl ether, ethyleneglycol monoethyl ether, ethylene glycol dimethyl ether, dimethoxydiethylether, tetrahydrofuran or dioxane; ketones, such as acetone, methylethyl ketone or methyl isobutyl ketone; alcohols, such as methanol,ethanol, propanol, isopropanol, butanol, ethylene glycol or glycerol;amides, such as N,N-dimethylformamide, N,N-diethylformamide,N,N-dimethylacetamide, N-methylpyrrolidone or hexamethylphosphoric acidtriamide; nitriles, such as acetonitrile or propionitrile; andsulfoxides, such as dimethyl sulfoxide. If the reaction in question iscarried out in the presence of a base, bases such as triethylamine,pyridine, N-methylmorpholine or N,N-diethylaniline in excess may alsoserve as solvent or diluent. If the reaction is carried out in thepresence of an acid catalyst, acids, for example strong organiccarboxylic acids, such as unsubstituted or substituted, e.g.halo-substituted, C₁-C₄alkanecarboxylic acids, for example formic acid,acetic acid or propionic acid, in excess may also serve as solvent ordiluent. Suitable solvents for the reaction in question can be takenfrom the Examples given below.

Variant (a):

The reaction is preferably carried out in a temperature range of from−20 to 160° C., especially from 0 to 100° C., customarily at from 25 to50° C.

Suitable solvents are especially: aliphatic and aromatic hydrocarbons,halogenated hydrocarbons, esters, nitriles, ethers; for example:petroleum ether, pentane, hexane, heptane, chlorobenzene, methylenechloride, ethylene chloride, bromochloromethane, chloroform, carbontetrachloride, tetrachloroethylene, ethyl acetate, acetonitrile, diethylether, diisopropyl ether, tetrahydrofuran, dioxane; or a mixturethereof; especially methylene chloride.

There are suitable as reagents especially water-removing,halide-containing agents, such as thionyl chloride (SOCl₂), thionylbromide (SOBr₂), phosphorus oxychloride (POCl₃), phosphorus oxybromide(POBr₃), phosphorus pentachloride or a sulfonic acid chloride orbromide; thionyl chloride is preferred.

Water or a base may be added to the reaction mixture, if desired;especially suitable bases are, for example, alkali metal or alkalineearth metal carbonates, alkali metal or alkaline earth metal hydrogencarbonates or alkali metal or alkaline earth metal hydroxides, or atertiary amine; in a preferred form the reaction is carried out withoutthe addition of a base.

Variant (b):

The reaction is preferably carried out in a temperature range of from−20 to 160° C., especially from 0 to 100° C., customarily from 0 to 25°C.

Suitable solvents are especially: aliphatic and aromatic hydrocarbons,halogenated hydrocarbons, esters, nitriles, ethers; for example:petroleum ether, pentane, hexane, heptane, chlorobenzene, methylenechloride, ethylene chloride, bromochloromethane, chloroform, carbontetrachloride, tetrachloroethylene, ethyl acetate, acetonitrile, diethylether, diisopropyl ether, tetrahydrofuran, dioxane; or a mixturethereof; methylene chloride is preferred.

Reagents: halide-containing water-removing agent, or sulfonylatingagent; for example: thionyl chloride, phosphorus oxychloride, phosphoruspentachloride, phosphorus oxytnbromide, triphenylphosphine+bromine; or asulfonic acid chloride or anhydride; customarily: thionyl chloride,triphenylphosphifle+bromine, toluenesulfonyl chloride, methanesulfonylchloride, trifluoromethanesulfonyl chloride or methanesulfonylanhydride.

Water or a base may be added to the reaction mixture, if desired;especially suitable bases are, for example, alkali metal or alkalineearth metal carbonates, alkali metal or alkaline earth metal hydrogencarbonates or alkali metal or alkaline earth metal hydroxides, or atertiary amine; in a preferred form the reaction is carried out withoutadditives.

Variant (c):

The reaction is preferably carried out in a temperature range of from−20 to 160° C., especially from 0 to 100° C., preferably from 50 to 70°C.

Suitable solvents are especially: aliphatic and aromatic hydrocarbons,halogenated hydrocarbons, esters, nitriles, ethers; for example:petroleum ether, pentane, hexane, heptane, chlorobenzene, methylenechloride, ethylene chloride, bromochloromethane, chloroform, carbontetrachloride, tetrachloroethylene, ethyl acetate, acetonitrile, diethylether, diisopropyl ether, tetrahydrofuran, dioxane; or a mixturethereof; tetrahydrofuran is especially preferred.

Variant (d):

The reaction is preferably carried out in a temperature range of from−20 to 160° C., especially from 0 to 100° C., preferably from 0 to 25°C.

Suitable solvents are especially: aliphatic and aromatic hydrocarbons,halogenated hydrocarbons, esters, amides, nitriles, ethers, alcohols,water, for example: petroleum ether, pentane, hexane, heptane,chlorobenzene, methylene chloride, ethylene chloride,bromochloromethane, chloroform, carbon tetrachloride,tetrachloroethylene, ethyl acetate, acetonitrile, diethyl ether,dimethylformamide, dimethylacetamide, diisopropyl ether,tetrahydrofuran, dioxane, ethanol, methanol, isopropanol, water, or amixture thereof; a mixture of water and ethanol is preferred.

An acid, a base or a buffer may be added to the reaction mixture, ifdesired; preference is given to a buffer having a pH of from 6 to 8,especially a phosphate buffer having a pH value of 7.

Variant (e):

The reaction is preferably carried out in a temperature range of from−20 to 160° C., especially from 0 to 100° C., preferably from 25 to 50°C.

Suitable solvents are especially: aliphatic and aromatic hydrocarbons,halogenated hydrocarbons, esters, amides, nitriles, ethers, alcohols,water, for example: petroleum ether, pentane, hexane, heptane,chlorobenzene, methylene chloride, ethylene chloride,bromochloromethane, chloroform, carbon tetrachloride,tetrachloroethylene, ethyl acetate, acetonitrile, diethyl ether,dimethylformamide, dimethylacetamide, diisopropyl ether,tetrahydrofuran, dioxane, ethanol, methanol, isopropanol, water, or amixture thereof; a mixture of water and ethanol is preferred.

Preferred acids for carrying out the reaction are inorganic acids, suchas hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,perchloric acid, tetrafluoroboric acid; carboxylic acids, such astrifluoroacetic acid; or sulfonic acids, such as toluenesulfonic acid,benzenesulfonic acid, camphorsulfonic acid; hydrochloric acid ispreferred.

Variant (f):

The reaction is preferably carried out in a temperature range of from−20 to 160° C., especially from 0 to 100° C., preferably from 0 to 25°C.

Suitable solvents are especially: hydrocarbons, esters, amides,nitriles, ethers, water; petroleum ether, pentane, hexane, heptane,ethyl acetate, acetonitrile, diethyl ether, dimethylformamide,dimethylacetamide, diisopropyl ether, tetrahydrofuran, dioxane, water;or a mixture thereof; ethyl acetate is preferred.

Suitable hydrogenation catalysts are, for example: metals or metaloxides, especially those of transition metals, especially also those onan inert support material; platinum oxide and nickel, especiallyplatinum oxide, are preferred. A Lewis acid is customarily added to thereaction mixture; especially suitable are halides of transition metals,especially iron(II) chloride.

Variant (g):

The reaction is preferably carried out in a temperature range of from−20 to 160° C., especially from 0 to 100° C., preferably from 50 to 80°C.

Suitable solvents are especially: aliphatic and aromatic hydrocarbons,halogenated hydrocarbons, esters, amides, nitriles, ethers, alcohols,water, for example: petroleum ether, pentane, hexane, heptane,chlorobenzene, methylene chloride, ethylene chloride,bromochloromethane, chloroform, carbon tetrachloride,tetrachloroethylene, ethyl acetate, acetonitrile, diethyl ether,dimethylformamide, dimethylacetamide, diisopropyl ether,tetrahydrofuran, dioxane, ethanol, methanol, isopropanol, water, or amixture thereof; acetonitrile is preferred.

Suitable alkylating agents are especially unsubstituted or substitutedalkyl halides or sulfonates; substituted or unsubstituted benzylchloride, bromide, mesylate or tosylate; substituted or unsubstitutedallyl chloride, bromide, mesylate or tosylate; substituted orunsubstituted propargyl chloride, bromide, mesylate or tosylate; estersor amides of bromoacetic acid or chloroacetic acid; especially benzylchloride, benzyl bromide, ethyl chloroacetate, ethyl bromoacetate, allylchloride, propargyl chloride; benzyl bromide is especially preferred.

Bases may be added to the reaction medium, if desired. Especiallysuitable are alkali metal or alkaline earth metal carbonates, hydrogencarbonates or hydroxides, or a tertiary amine; potassium carbonate isespecially preferred.

Variant (h):

The reaction is preferably carried out in a temperature range of from−20 to 160° C., especially from 0 to 100° C., preferably from 25 to 50°C.

Suitable solvents are especially: aliphatic and aromatic hydrocarbons,halogenated hydrocarbons, ethers; for example: petroleum ether, pentane,hexane, heptane. chlorobenzene, methylene chloride, ethylene chloride,bromochloromethane, chloroform, carbon tetrachloride,tetrachloroethylene, diethyl ether, diisopropyl ether, tetrahydrofuran,dioxane; or a mixture thereof; it is especially preferred to carry outthe process without a solvent.

There is preferably used as the reagent a mixture of phosphorusoxychloride and dimethylformamide.

Salts of compounds of formulae (I) to (IV), (VI) and (A) to (C) can beprepared in a manner known per se. For example, acid addition salts areobtained by treatment with a suitable acid or a suitable ion exchangereagent, and salts with bases are obtained by treatment with a suitablebase or a suitable ion exchange reagent.

Salts of compounds of formulae (I) to (IV), (VI) to (VIII) and (A) to(C) can be converted into the corresponding free compounds in customarymanner; acid addition salts, for example, by treatment with a suitablebasic agent or a suitable ion exchange reagent, and salts with bases,for example, by treatment with a suitable acid or a suitable ionexchange reagent.

Salts of compounds of formulae (I) to (IV), (VI) to (VIII) and (A) to(C) can be converted into different salts of compounds of thecorresponding formulae in a manner known per se; acid addition salts,for example, can be converted into different acid addition salts, forexample by treating a salt of an inorganic acid, such as ahydrochloride, with a suitable metal salt, such as a sodium, barium orsilver salt, of an acid, for example silver acetate, in a suitablesolvent in which an inorganic salt that forms, for example silverchloride, is insoluble and therefore separates out of the reactionmixture.

Depending on the procedure and the reaction conditions, the compounds offormulae (I) to (IV), (VI) to (VIII) and (A) to (C) having salt-formingproperties can be obtained in free form or in the form of salts.

The compounds of formulae (I) to (IV), (VI) to (VIII) and (A) to (C) andin each case, where applicable, their tautomers, in each case in freeform or in salt form, may be in the form of one of the possible isomersor in the form of a mixture thereof, for example, depending on thenumber of asymmetric carbon atoms occurring in the molecule and theirabsolute and relative configuration, and/or depending on theconfiguration of non-aromatic double bonds occurring in the molecule, inthe form of pure isomers, such as antipodes and/or diastereoisomers, orin the form of mixtures of isomers, such as mixtures of enantiomers, forexample racemates, mixtures of diastereoisomers or mixtures ofracemates; the invention relates both to the pure isomers and to allpossible mixtures of isomers and is to be interpreted as suchhereinbefore and hereinafter, even if stereochemical details are notmentioned specifically in every case.

Mixtures of enantiomers, such as racemates, that are obtainable in acorresponding manner can be resolved into the optical antipodes by knownmethods, for example by recrystallization from an optically activesolvent, by chromatography on chiral adsorbents, for example highpressure liquid chromatography (HPLC) on acetylcellulose, with the aidof suitable microorganisms, by cleavage with specific, immobilisedenzymes, via the formation of inclusion compounds, for example usingchiral crown ethers, only one enantiomer being complexed, or byconversion into diastereoisomeric salts, for example by reaction of abasic end-product racemate with an optically active acid, such as acarboxylic acid, for example camphoric, tartaric or malic acid, or asulfonic acid, for example camphorsulfonic acid, and separation of themixture of diastereoisomers so obtained, for example on the basis oftheir different solubilities by fractional crystallisation, into thediastereoisomers, from which the desired enantiomer can be freed by theaction of suitable, for example basic, agents.

Mixtures of diastereoisomers and mixtures of racemates of compounds offormulae (I) to (IV), (VI) to (VIII) and (A) to (C) which may beobtained by the process according to the starting materials andprocedures chosen, or which are obtainable by another method, or theirsalts, can be separated into the pure diastereoisomers or racemates inknown manner on the basis of the physico-chemical differences betweenthe constituents, for example by means of fractional crystallisation,distillation and/or chromatography.

Apart from by separation of corresponding mixtures of isomers, purediastereoisomers and enantiomers can be obtained according to theinvention also by generally known methods of diastereoselective andenantioselective synthesis, for example by carrying out the processaccording to the invention using starting materials havingcorrespondingly suitable stereochemistry.

The compounds of formulae (I) to (IV), (VI) to (VIII) and (A) to (C) andtheir salts can also be obtained in the form of their hydrates and/orinclude other solvents, for example solvents that may have been used forthe crystallisation of compounds that occur in solid form.

The invention relates to all those forms of the process according towhich a compound obtainable as starting material or intermediate at anystage of the process is used as starting material and all or some of theremaining steps are carried out, or a starting material is used in theform of a derivative or salt and/or in the form of its racemates orantipodes or, especially, is formed under the reaction conditions.

Compounds of formulae (I) to (IV) and (A) to (C) obtainable inaccordance with the process or by another method can be converted intodifferent compounds of formulae (I) to (IV) and (A) to (C) in a mannerknown per se.

In the processes of the present invention there are preferably usedthose starting materials and intermediates, in each case in free form orin salt form, which lead to the compounds of formulae (I) to (IV), (VI)to (VIII) and (A) to (C) described at the beginning as being especiallyvaluable, their salts or their acid addition products.

The invention relates especially to the preparation processes describedin preparation processes P1 to P5.

The present invention relates also to the compounds of formula (II) and,where applicable, their E/Z-isomers, mixtures of E/Z-isomers and/ortautomers, in each case in free form or in salt form, wherein A is asdefined above for formula (I).

The present invention relates also to the compounds of formula (III)and, where applicable, their E/Z-isomers, mixtures of E/Z-isomers and/ortautomers, in each case in free form or in salt form, wherein A is asdefined above for formula (I).

The present invention relates also to the compounds of formula (IV) and,where applicable, their E/Z-isomers, mixtures of E/Z-isomers and/ortautomers, in each case in free form or in salt form, wherein R, R₂ andR₃ are as defined above. Preference is given to compounds of formula(IV) wherein R₂ and R₃ are each independently of the other C₁-C₄alkyl ortwo radicals R₂ and R₃, together with the nitrogen atom to which theyare bonded, form a five- or six-membered ring in which a —CH₂— group hasoptionally been replaced by a hetero atom selected from the groupconsisting of O and S, or by NH, and wherein the five- or six-memberedring is unsubstituted or is mono- or di-substituted by C₁-C₄alkyl;especially, R₂ and R₃ together form —(CH₂)₅— or —(CH₂)₂—O—(CH₂)₂—.

The present invention relates also to the compounds of formula (VI) and,where applicable, their E/Z-isomers, mixtures of E/Z-isomers and/ortautomers, in each case in free form or in salt form, wherein R is asdefined above for formula (I), with the proviso that A is notunsubstituted C₁-C₂alkyl.

For substituents R in the compounds of formulae (II), (III), (IV) and(VI) and in the compound R—X₂, the same preferred meanings as mentionedabove in the processes for the preparation of the compounds of formula(I) apply.

The compounds of formulae (A), (B) and (C) are known.

PREPARATION EXAMPLES Example P1a2-Benzylsulfanyl-thiazole-5-carbaldehyde

180 mg of dimethylformamide and 130 mg of phosphorus oxychloride areadded at room temperature to 200 mg of 2-benzylmercaptothiazole, and themixture is stirred at 40° C. for 6 hours. Ice-water is then added to thereaction mixture, extraction with ethyl acetate is carried out, and theorganic phase is dried over sodium sulfate and concentrated in vacuo.

Column chromatography on silica gel yields2-benzylsulfanyl-thiazole-5-carbaldehyde in the form of an oil (compound1.1).

Example P1b

The other compounds listed in table 1 can also be prepared in a manneranalogous to that described in Example P1 a.

TABLE 1 Compounds of the formula

Comp. No. R Physical data 1.1 benzyl oil 1.2 phenyl 1.3 cyclohexyl 1.4

1.5 CH₂═CH—CH₂— 1.6 ClCH═CH—CH₂— 1.7 CH₂═C(CH₃)—CH₂— 1.8 CH₂═CH—CH₂—CH₂—1.9 2-chlorobenzyl 1.10 4-chlorobenzyl 1.11 CH≡C—CH₂— 1.12 isopropyl1.13 C₂H₅—OC(═O)—CH₂— 1.14

1.15 n-C₃H₇— 1.16 HO—CH₂—CH₂— 1.17 tert-butyl 1.18 n-C₁₂H₂₅— 1.192-ethyl-pentyl

Example P2a 4-(2-Benzylsulfanyl-thiazol-5-ylmethyl)-morpholine

1.2 g of 5-morpholin-4-ylmethyl-3H.-thiazole-2-thione and 2.0 g ofpotassium carbonate are placed in 50 ml of acetonitrile; 1.0 g of benzylbromide is added and stirring is then carried out at 70° C. for 90minutes. The mixture is allowed to cool and is filtered, and the solventis removed by evaporation. The residue crystallizes from diisopropylether. In that manner 4-(2-benzylsulfanyl-thiazol-5-ylmethyl)-morpholinehaving a melting point of 103-104° C. is obtained (compound 2.1).

Example P2b

The other compounds listed in Table 2 can also be prepared in a manneranalogous to that described in Example P2a.

TABLE 2 Compounds of the formula

Comp. No. R R₂ R₃ melting point 2.1 benzyl —CH₂—CH₂—O—CH₂—CH₂— 103-104°C. 2.2 phenyl —CH₂—CH₂—O—CH₂—CH₂— 2.3 cyclohexyl —CH₂—CH₂—O—CH₂—CH₂— 2.4

—CH₂—CH₂—O—CH₂—CH₂— 2.5 CH₂═CH—CH₂— —CH₂—CH₂—O—CH₂—CH₂— 2.6 ClCH═CH—CH₂——CH₂—CH₂—O—CH₂—CH₂— 2.7 CH₂═C(CH₃)—CH₂— —CH₂—CH₂—O—CH₂—CH₂— 2.8CH₂═CH—CH₂—CH₂— —CH₂—CH₂—O—CH₂—CH₂— 2.9 2-chlorobenzyl—CH₂—CH₂—O—CH₂—CH₂— 2.10 4-chlorobenzyl —CH₂—CH₂—O—CH₂—CH₂— 2.11CH≡C—CH₂— —CH₂—CH₂—O—CH₂—CH₂— 2.12 isopropyl —CH₂—CH₂—O—CH₂—CH₂— 2.13C₂H₅—OC(═O)—CH₂— —CH₂—CH₂—O—CH₂—CH₂— 2.14

—CH₂—CH₂—O—CH₂—CH₂— 2.15 n-C₃H₇— —CH₂—CH₂—O—CH₂—CH₂— 2.16 HO—CH₂—CH₂——CH₂—CH₂—O—CH₂—CH₂— 2.17 tert-butyl —CH₂—CH₂—O—CH₂—CH₂— 2.18 n-C₁₂H₂₅——CH₂—CH₂—O—CH₂—CH₂— 2.19 2-ethyl-pentyl —CH₂—CH₂—O—CH₂—CH₂— 2.20 Benzyl—CH₂—CH₂—CH₂—CH₂—CH₂— 2.21 Phenyl —CH₂—CH₂—CH₂—CH₂—CH₂— 2.22 Cyclohexyl—CH₂—CH₂—CH₂—CH₂—CH₂— 2.23 Benzyl —CH₂—CH₂—CH₂—CH₂— 2.24 Phenyl—CH₂—CH₂—CH₂—CH₂— 2.25 Cyclohexyl —CH₂—CH₂—CH₂—CH₂— 2.26 Benzyl—CH₂—CH₂—N(CH₃)—CH₂—CH₂— 2.27 Phenyl —CH₂—CH₂—N(CH₃)—CH₂—CH₂— 2.28Cyclohexyl —CH₂—CH₂—N(CH₃)—CH₂—CH₂— 2.29 Benzyl —CH₃ 2.30 Phenyl —CH₃2.31 Cyclohexyl —CH₃ 2.32 Benzyl —C₂H₅ 2.33 Phenyl —C₂H₅ 2.34 Cyclohexyl—C₂H₅

Example P3 2-Benzylsulfanyl-5-hydroxymethyl-thiazole

a) 0.2 ml of concentrated hydrochloric acid is added to 3.0 g of2-benzylsulfanyl-5-hydroxy-methyl-4,5-dihydrothiazol-4-ol in 25 ml ofethanol. The mixture is stirred at 50° C. for 12 hours, the solvent isremoved in vacuo, and the residue is chromatographed on silica gel(ethethexane; 1:1). The title compound is obtained in the form of ayellow oil (compound 3.1).

b) 325 mg of 2-benzylsulfanyl-thiaZole-5-cathaldehyde in 35 ml of ethylacetate are hydrogenated with 14 mg of FeCl2×4H₂O and 175 mg of platinumoxide under normal pressure for 64 hours at room temperature under ahydrogen atmosphere. The reaction mixture is filtered off and extractedwith water. The organic phase is dried over sodium sulfate andconcentrated in vacuo. The title compound is obtained in the form of anoil (compound 3.1).

Example P3c

The other compounds listed in Table 3 can also be prepared in a manneranalogous to that described in Examples P3a and P3b.

TABLE 3 Compounds of the formula

Comp. No. R Physical data 3.1 benzyl oil 3.2 phenyl 3.3 cyclohexyl 3.4

3.5 CH₂═CH—CH₂— 3.6 ClCH═CH—CH₂— 3.7 CH₂═C(CH₃)—CH₂— 3.8 CH₂═CH—CH₂—CH₂—3.9 2-chlorobenzyl 3.10 4-chlorobenzyl 3.11 CH≡C—CH₂— 3.12 isopropyl3.13 C₂H₅—OC(═O)—CH₂— 3.14

3.15 n-C₃H₇— 3.16 HO—CH₂—CH₂— 3.17 tert-butyl 3.18 n-C₁₂H₂₅— 3.192-ethyl-pentyl

Example P4a 2-Benzylsulfanyl-5-hydroxymethyl-4,5-dihydrothiazol-4-ol

1.1 g of dithiocarbamic acid benzyl ester are suspended in a mixture of6 ml of phosphate buffer (pH=7.0) and 6 ml of ethanol, and the resultingsuspension is added dropwise at 0° C. to 6 ml of a 2M solution ofglycidyl aldehyde in water. Stirring is carried out at room temperaturefor 12 hours, and then the ethanol is removed in vacuo. The aqueousphase is extracted twice with dichloromethane, and the combined organicphases are washed with saturated aqueous sodium chloride solution anddried over magnesium sulfate. After removal of the solvent,2-benzylsulfanyl-5-hydroxymethyl-4,5dihydrothiazol-4-ol having a meltingpoint of 80-82° C. is obtained (compound 4.1).

Example P4b

The other compounds listed in Table 4 can also be prepared in a manneranalogous to that described in Example P4a.

TABLE 4 Compounds of the formula

Comp. No. R Physical data 4.1 benzyl m.p.: 80- 82° C. 4.2 phenyl 4.3cyclohexyl 4.4

4.5 CH₂═CH—CH₂— 4.6 ClCH═CH—CH₂— 4.7 CH₂═C(CH₃)—CH₂— 4.8 CH₂═CH—CH₂—CH₂—4.9 2-chlorobenzyl 4.10 4-chlorobenzyl 4.11 CH≡C—CH₂— 4.12 isopropyl4.13 C₂H₅—OC(═O)—CH₂— 4.14

4.15 n-C₃H₇— 4.16 HO—CH₂—CH₂— 4.17 tert-butyl 4.18 n-C₁₂H₂₅— 4.192-ethyl-pentyl

Example P5 2-Benzylsulfanyl-5-chloromethyl-thiazole (compound 5.1)

a) To 1.4 g of 2-benzylsulfanyl-5-hydroxymethyl-4,5-dihydrothiazol-4-olsuspended in 5 ml of dichloromethane, 0.96 ml of thionyl chloridedissolved in 5 ml of dichloromethane are added dropwise at 0° C.Stirring is then carried out at room temperature for 3 hours. Themixture is diluted with 10 ml of ethyl acetate and the organic phase iswashed twice with saturated aqueous sodium hydrogen carbonate solutionand dried over magnesium sulfate. After removal of the solvent in vacuo,2-benzylsulfanyl-5-chloromethyl-thiazole having a melting point of57-61° C. is obtained.

b) To 1.18 g of 2-benzylsulfanyl-5-hydroxymethyl-thiazole dissolved in 5ml of dichloromethane, 0.4 ml of thionyl chloride dissolved in 5 ml ofdichloromethane are added dropwise at 0° C. to. The reaction mixture isthen allowed to warm to room temperature and stirred for 0.5 hour. Afterthe addition of 5 ml of water, the organic phase is washed twice withsaturated aqueous sodium hydrogen carbonate solution and dried overmagnesium sulfate. After removal of the solvent in vacuo, chromatographyon silica gel (ether:hexane; 1:4) yields2-benzylsulfanyl-5-chloromethyl-thiazole having a melting point of57-61° C.

c) 5.5 ml of chloroformic acid ethyl ester are added to 8.0 g of4-(2-benzylsulfanyl-thiazol-5-ylmethyl)-morpholine in 60 ml oftetrahydrofuran, and the mixture is heated at reflux for 5 hours. Themixture is then cooled to room temperature, the solvent is removed byevaporation in vacuo and the residue is purified by chromatography onsilica gel with ether-hexane 1:2.

2-Benzylsulfanyl-5-chloromethylthiazole having a melting point of 57-59°C. is obtained.

Example P5d

The other compounds listed in Table 5 can also be prepared in a manneranalogous to that described in Examples P5a to P5c.

TABLE 5 Compounds of the formula

Comp. No. R X Physical data 5.1 benzyl Cl m.p.: 57- 59° C. 5.2 benzyl Br5.3 phenyl Cl 5.4 cyclohexyl Br 5.5

Cl 5.6 CH₂═CH—CH₂— Cl 5.7 ClCH═CH—CH₂— Cl 5.8 CH₂═C(CH₃)—CH₂— Cl 5.9CH₂═CH—CH₂—CH₂— Cl 5.10 2-chlorobenzyl Cl 5.11 4-chlorobenzyl Cl 5.12CH≡C—CH₂— Cl 5.13 isopropyl Cl 5.14 C₂H₅—OC(═O)—CH₂— Cl 5.15

Cl 5.16 n-C₃H₇— Cl 5.17 HO—CH₂—CH₂— Cl 5.18 tert-butyl Cl 5.19 n-C₁₂H₂₅—Cl 5.20 2-ethyl-pentyl Cl 5.21 isopropyl Br 5.22 C₂H₅—OC(═O)—CH₂— Br5.23

Br 5.24 n-C₃H₇— Br 5.25 HO—CH₂—CH₂— Br 5.26 tert-butyl Br 5.27 n-C₁₂H₂₅—Br 5.28 2-ethyl-pentyl Br

1. A process for the preparation of a compound of the formula

and, where applicable, its E/Z-isomers, mixtures of E/Z-isomers and/ortautomers and acid addition products thereof, in each case in free formor in salt form, wherein: R is unsubstituted or substituted C₁-C₁₂alkyl,unsubstituted or substituted C₂-C₄alkenyl, unsubstituted or substitutedC₂-C₄alkynyl, unsubstituted or substituted C₃-C₆cycloalkyl,unsubstituted or substituted aryl, unsubstituted or substitutedheteroaryl, or —SR₁; R₁ is unsubstituted or substituted C₁-C₁₂alkyl,unsubstituted or substituted C₂-C₄alkenyl, unsubstituted or substitutedC₂-C₄alkynyl, unsubstituted or substituted cycloalkyl, unsubstituted orsubstituted aryl or unsubstituted or substituted heteroaryl; and X ishalogen; said process comprising, reacting a compound of the formula

or, where applicable, an E/Z-isomer, a mixture of E/Z-isomers and/or atautomer or an acid addition product thereof, in each case in free formor in salt form, with a compound having a formula selected from thegroup consisting of halogen-C(═O)—O—C₁-C₈alkyl; halogen-C(═O)—O-aryl;and halogen-C(═O)—O-benzyl; wherein: R is as defined for formula (I); R₂and R₃ are each independently of the other H, C₁-C₆alkyl,C₃-C₆cycloalkyl, phenyl or benzyl or, together with the nitrogen atom towhich they are bonded, form a five- to seven-membered ring in which a—CH₂-group has optionally been replaced by a hetero atom selected fromthe group consisting of O and S, or by NR₉, and wherein the carbon-chainof the five- to seven-membered ring is unsubstituted or is mono- ordi-substituted by C₁-C₄alkyl; and R₉ is an organic radical.
 2. A processaccording to claim 1, wherein R in the compounds of formulae (I) and(IV) is unsubstituted or halo- or hydroxy-substituted C₁-C₁₂alkyl,unsubstituted or halo-substituted aryl-C₁-C₄alkyl, unsubstituted orhalo-substituted heteroaryl-C₁-C₄alkyl, aryl-C₂-C₄alkenyl,heteroaryl-C₂-C₄alkenyl, unsubstituted or halo-substituted C₂-C₄alkenyl,C₂-C₄alkynyl, aryl-C₂-C₄alkynyl, heteroaryl-C₂-C₄alkynyl,C₄-C₆cycloalkyl, unsubstituted or halo-substituted aryl, unsubstitutedor halo-substituted heteroaryl, —CH₂—COO—C₁-C₈alkyl, —CH₂—CO—C₁-C₈alkyl,SR₁ or —CH₂—COO-M, wherein M is hydrogen or a cation.
 3. A processaccording to claim 1, wherein: R in the compounds of formulae (I) and(IV) is —(CH₂)_(n)—SR₁; R₁ is C₁-C₈alkyl, aryl-C₁-C₄-alkyl,heteroaryl-C₁-C₄alkyl, C₂-C₄alkenyl, aryl-C₂-C₄alkenyl,heteroaryl-C₂-C₄alkenyl, C₂-C₄-alkynyl, aryl-C₂-C₄alkynyl,heteroaryl-C₂-C₄alkynyl, cyclohexyl, aryl, heteroaryl or heteroarylwhich is substituted with —CH2-X₁, or formyl; and n is an integerselected from 1 to
 8. 4. A process for the preparation of a compound ofthe formula

and, where applicable, its E/Z-isomers, mixtures of E/Z-isomers and/ortautomers and acid addition products thereof, in each case in free formor in salt form, wherein; R is unsubstituted or substituted heteroaryl,or —SR₁; R₁ is unsubstituted or substituted C₁-C₁₂alkyl, unsubstitutedor substituted C₂-C₄alkenyl, unsubstituted or substituted C₂-C₄alkynyl,unsubstituted or substituted cycloalkyl, unsubstituted or substitutedaryl or unsubstituted or substituted heteroaryl; and X is halogen saidprocess comprising, reacting a compound of the formula

or, where applicable, an E/Z-isomer, a mixture of E/Z-isomers and/or atautomer or an acid addition product thereof, in each case in free formor in salt form, with a compound having a formula selected from thegroup consisting of halogen-C(═O)—O—C₁-C₈alkyl, halogen-C(═O)—O-aryl,and halogen-C(═O)—O-benzyl; wherein: R is as defined for formula (I); R₂and R₃ are each independently of the other H, C₁-C₆alkyl,C₃-C₆cycloalkyl, phenyl or benzyl or, together with the nitrogen atom towhich they are bonded, form a five- to seven-membered ring in which a—CH₂-group has optionally been replaced by a hetero atom selected fromthe group consisting of O and S, or by NR₉, and wherein the carbon-chainof the five- to seven-membered ring is unsubstituted or is mono- ordi-substituted by C₁-C₄alkyl; and R₉ is an organic radical.